Aryl-Substituted Polymyxin Derivatives With Lower Renal Toxicity
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Solution Overview
Problem
Existing polymyxin compounds used for parenteral therapy of systemic infections exhibit high cytotoxicity and renal toxicity, limiting their effectiveness and safety.
Innovation Solution
Development of polymyxin derivatives with a deacylated core and specific amino acid substitutions, particularly at position 3 with Dap, and a γ-aminopropyl group at the N-terminal, balanced with acceptable kidney drug levels and lower cytotoxicity, enhancing antibacterial activity against Gram-negative bacteria.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymyxin compounds are used for parenteral therapy of systemic infections, then antibacterial activity is achieved, but cytotoxicity and renal toxicity are high
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of polymyxin compounds through specific substitutions: replacing the N-terminal fatty acyl moiety and adjacent diaminobutyric acid with a terminal group having an amino substituent, and substituting amino acid residues at positions 6 and/or 7. These structural parameter changes result in derivatives that maintain antibacterial activity while exhibiting reduced cytotoxicity and renal toxicity compared to parent polymyxin B and colistin.
Solution Approach 2:
The patent creates composite structures by combining modified N-terminal groups with substituted amino acid residues at positions 6 and/or 7 on the polymyxin core. This composite approach, where multiple structural modifications work together, produces derivatives with optimized properties that balance antibacterial efficacy against Gram-negative bacteria with reduced toxic effects on mammalian cells and kidneys.
2Object-affected harmful factors
If polymyxin derivatives with reduced cytotoxicity are developed, then safety is improved, but antibacterial activity may be reduced
Solution Approach 1:
The patent applies local quality by making specific localized modifications to the polymyxin structure: the N-terminal region is replaced with a terminal group having an amino substituent, and amino acid residues at positions 6 and/or 7 are substituted. These localized changes selectively reduce cytotoxicity while preserving the core antibacterial mechanism, achieving a balance where safety is improved without sacrificing therapeutic efficacy against Gram-negative bacteria.
3Object-affected harmful factors
If compounds with lower cytotoxicity are developed, then safety profile is improved, but kidney drug levels may increase leading to renal toxicity
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure to achieve a dual effect: the terminal group with amino substituent and amino acid substitutions at positions 6 and/or 7 not only reduce cytotoxicity but also optimize pharmacokinetic properties to maintain acceptable kidney drug levels. This structural optimization ensures that compounds with improved safety profiles do not accumulate to toxic levels in renal tissue.
Data Source
AI summary
The invention provides a polymyxin compound of formula (I) and salts, solvates and protected forms thereof, pharmaceutical compositions comprising the compounds of formula (I), and the use of the compounds and compositions in methods of treatment, such as methods for the treatment of microbial infections. The compounds of formula (I) are represented thus:wherein —R15 is a group:and —R16 is hydrogen; —R17 is hydrogen; -L- is a covalent bond or methylene; and —Ar is optionally substituted aryl. The groups —X—, —R1, —R2, —R3, —R4, and —R8 are as defined herein.